Synthesis and Biological Activity of Novel Acridinylidene and Benzylidene Thiazolidinediones.

Mourão, Rosa Helena Veras; Silva, T. G.; Soares, A. L. M.; Vieira, Erika Souza; Santos, Juliette Noadya Costa; Lima, Maria Alice Gomes de Andrade; Lima, Vera L. M.; Galdino, Suely Lins; Barbe, Jacques; Pitta, Ivan R.

doi:10.1002/chin.200608100

Cited by 8 publications

(10 citation statements)

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“…GQ‐130 was synthesized by the Department of Antibiotics at the Federal University of Pernambuco, Recife, Brazil, according to a previously described methodology . GQ‐130 or 5‐(4‐chloro‐benzylidene)‐3‐(2,4‐dichloro‐benzyl)‐thiazolidine‐2,4‐dione (Figure ) which has purity of over 98%, is a white to beige powder with the determined formula of C 15 H 11 Cl 3 NO 2 S, and chemical structure identified as being the compound GQ‐130.…”

Section: Methodsmentioning

confidence: 99%

GQ‐130, a novel analogue of thiazolidinedione, improves obesity‐induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway

Silva

Ribeiro-Filho

Avelino

et al. 2020

Clin Exp Pharma Physio

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The present investigation aimed to characterize the effect of a short‐time treatment with a new thiazolidinedione (TZD) derivative, GQ‐130, on metabolic alterations in rats fed a high‐fat diet (HFD). We investigated whether metabolic alterations induced by GQ‐130 were mediated though a mechanism that involves PPARβ/δ transactivation. Potential binding and transactivation of PPARα, PPARβ/δ or PPARγ by GQ‐130 were examined through cell transactivation, 8‐anilino‐1‐naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay. For in vivo experiments, male 8‐week‐old Wistar rats were divided into three groups fed for 6 weeks with: (a) a standard rat chow (14% fat) (control group), (b) a HFD (57.8% fat) alone (HFD group), or (c) a HFD associated with an oral treatment with GQ‐130 (10 mg/kg/d) during the last week (HFD‐GQ group). In 293T cells, unlike rosiglitazone, GQ‐130 did not cause significant transactivation of PPARγ but was able to activate PPARβ/δ by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ‐130 does not bind directly to PPARβ/δ binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPARβ/δ in the presence of GQ‐130. Compared to the control group, rats of the HFD group showed obesity, increased systolic blood pressure (SBP), insulin resistance, impaired glucose intolerance, hyperglycaemia, and dyslipidaemia. GQ‐130 treatment abolished the increased SBP and improved all metabolic dysfunctions observed in the HFD group. Oral treatment with GQ‐130 was effective in improving HFD‐induced metabolic alterations probably through a mechanism that involves PPARβ/δ activation.

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Section: Methodsmentioning

confidence: 99%

GQ‐130, a novel analogue of thiazolidinedione, improves obesity‐induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway

Silva

Ribeiro-Filho

Avelino

et al. 2020

Clin Exp Pharma Physio

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“…The chemical data and synthetic procedures for (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)thiazolidine-2,4-dione (AC-4), (5ZE)-5-acridin-9-ylmethylene-3-(4bromo-benzyl)-thiazolidine-2,4-dione (AC-7), (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl)-1,3-thiazolidine-2,4-dione (AC-10) and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2,4-dione (AC-23) are reported elsewhere (Barros et al, 2012;Mourão et al, 2005;Silva et al, 2001). Thiazolidine-2,4-dione was N-(3)-alkylated in the presence of potassium hydroxide, which enabled the thiazolidine potassium salt to react with the substituted benzylhalide in a hot alcohol medium.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives

Barros

Bezerra

Ferreira

et al. 2013

Toxicology and Applied Pharmacology

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Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9-ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione - AC-4; (5ZE)-5-acridin-9-ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione - AC-7; (5Z)-5-(acridin-9-ylmethylene)-3-(4-chloro-benzyl)-1,3-thiazolidine-2,4-dione - AC-10; and (5ZE)-5-(acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2,4-dione - AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin-eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways.

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“…Next, 2-cyano-3-(4-chlorophenyl)-acrylic acid ethyl ester (Figure 1, no. 4;Mourão et al, 2005) was synthesized through Knoevenagel condensation between 4-chlorobenzaldehyde and ethyl cyanoacetate. A Michael addition was performed by reacting the (E)-3-(3-bromophenyl)-2-ethoxyacrylonitrile ( Figure 1, no.…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

Ability of two new thiazolidinediones to downregulate proinflammatory cytokines in peripheral blood mononuclear cells from children with asthma

Rêgo

Azoubel-Antunes

Bezerra

et al. 2018

Braz. J. Pharm. Sci.

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Allergic asthma is a chronic, complex inflammatory disease of the airway. Despite extensive studies on the immunomodulation of T helper (Th) cell pathways (i.e., Th1 and Th2) in asthma, little is known about the effects of Th17 pathway modulation, particularly that involving peroxisome proliferator-activated receptors (PPARs). In response, two new thiazolidinedione derivatives-namely, LPSF-GQ-147 and LPSF-CR-35 were synthesized and evaluated for their immunomodulatory effects on Th17-related cytokines, including interferon γ (IFNγ), interleukin IL-6, IL-17, and IL-22 in the peripheral blood mononuclear cells of asthmatic children. Both compounds were nontoxic even at high concentrations (i.e., 100 µM). The LPSF-CR-35 compound significantly reduced the levels of IL-17A (p = .039) and IFNγ (p = .032) at 10 µM. For IL-22 and IL-6, significant reduction occurred at 100 µM (p = .039 and p = .02, respectively). Conversely, LPSF-GQ-147 did not significantly inhibit the production of the tested cytokines, the levels of all of which were more efficiently reduced by LPSF-CR-35 than methylprednisolone, the standard compound. Real-time polymerase chain reaction assay confirmed that LPSF-GQ-147 has significant PPARγ modulatory activity. Such data indicate that both LPSF-CR-35 and LPSF-GQ-147 are promising candidates as drugs for treating inflammation and asthma.

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Synthesis and Biological Activity of Novel Acridinylidene and Benzylidene Thiazolidinediones.

Cited by 8 publications

References 1 publication

GQ‐130, a novel analogue of thiazolidinedione, improves obesity‐induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway

GQ‐130, a novel analogue of thiazolidinedione, improves obesity‐induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway

Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives

Ability of two new thiazolidinediones to downregulate proinflammatory cytokines in peripheral blood mononuclear cells from children with asthma

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